HMGB1 upregulates NF-kB by inhibiting IKB-α and associates with diabetic retinopathy
Introduction
Diabetic retinopathy (DR), a major microvascular complication of diabetes mellitus (DM), is the main cause of blindness in adults [[1], [2], [3]]. Because the extremely complicated pathogenesis of DR has not been fully elucidated, investigating and finding new therapeutic targets for DR is necessary. The main pathological changes of DR include retinal cell apoptosis and angiogenesis [4]. Previous studies have shown that progression of DR is accompanied by oxidative stress [5], mitochondrial dysfunction [6], and inflammation [7] as well as other clinical manifestations.
High-mobility group box 1 (HMGB1) protein is a highly conserved non-histone DNA-binding protein that plays an important role in many biological behaviors. As a late inflammatory factor, HMGB1 can be released into extracellular fluid actively or passively after stress [8,9]. In the cytoplasm, HMGB1 is involved in the imbalance of autophagy and apoptosis [10]. When released, HMGB1 can regulate angiogenesis [11], cell metastasis, and release of inflammatory cytokines [[12], [13], [14]].
Recent studies [15,16] have shown that HMGB1 is associated with diabetic peripheral neuropathy and involved in the occurrence and progression of DR; however, the underlying mechanism remains unclear. Therefore, in the present study, the specific effects of HMGB1 and its mechanism in DR were investigated.
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Animals and groups
Forty specific-pathogen-free (SPF) male Sprague Dawley (SD) rats weighing 240–280 g were selected and randomly divided into the normal or DM group. All animal experiments were approved by the Ethics Committee of the Affiliated Hospital of China Medical University (ethics number: 2016PS229K). Rats in the DM group were injected intraperitoneally with 1% streptozototocin (STZ, Sigma, USA) at the dose of 60 mg/kg, and the rats in the normal group were injected intraperitoneally with an equal amount
Animal model
Weight and blood glucose were not significantly different among the control, HMGB1, DM combined with HMGB1 siRNA, and DM groups (p > 0.05). After 72 h of injection with STZ, the blood glucose in rats in both the DM combined with HMGB1 siRNA and DM groups increased to >16.7 mmol/L, indicating the establishment of the DM model was 100% successful. By comparison, the weight of rats in the DM combined with HMGB1 siRNA and DM groups was lower than in the control and HMGB1 groups (all p < 0.05);
Proliferation and apoptosis
After the overexpression of HMGB1, CCK-8 was used to investigate the impact of HMGB1 on proliferation of the HREC line. Cell proliferation in the sh-HMGB1 transfection group was lower than in the sh-NC transfection group (Fig. 4B). Flow cytometry results showed the apoptosis rate in the sh-HMGB1 transfection group was higher than in the sh-NC transfection group (Fig. 4A).
Discussion
HMGB1, a multifunctional protein, is associated with a variety of physiological and pathological processes, including cell proliferation and differentiation, inflammation, immunity, cancer, metabolism, and oxidative stress [[17], [18], [19], [20], [21]]. However, information regarding the function of HMGB1 in DR is relatively limited. In the present study, the HMGB1 expression in the retinas of diabetic rats at 17 weeks of age was higher than in the control group. After HREC were treated for
Conclusions
In conclusion, the results from this study showed that HMGB1 may affected the NF-kB pathway through IKB-α, thus affecting the pathogenesis of DR, and the inhibition of HMGB1 may provide a novel concept for the treatment of DR.
The following are the supplementary data related to this article.
Funding
This work was partly supported by the National Natural Science Foundation of China (81570866).
Ethics approval and consent to participate
Animal experimental procedures were in accordance with institutional guidelines and approved by the Ethics Committee of the Affiliated Hospital of China Medical University (ethics number: 2016PS229K).
Declaration of competing interest
The authors declare that there are no conflicts of interest.
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